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Zurich Open Repository andArchiveUniversity of ZurichMain LibraryStrickhofstrasse 39CH-8057 Zurichwww.zora.uzh.ch
Year: 2014
Luminal matrices: An inside view on organ morphogenesis
Luschnig, Stefan ; Uv, Anne
Abstract: Tubular epithelia come in various shapes and sizes to accommodate the specific needs fortransport, excretion and absorption in multicellular organisms. The intestinal tract, glandular organsand conduits for liquids and gases are all lined by a continuous layer of epithelial cells, which formthe boundary of the luminal space. Defects in epithelial architecture and lumen dimensions will impairtransport and can lead to serious organ malfunctions. Not surprisingly, multiple cellular and molecularmechanisms participate in controlling size and form of tubular epithelial structures. One intriguing aspectof epithelial organ formation is the coordinate behavior of individual cells as they mold the mature lumen.Here, we focus on recent findings, primarily from Drosophila, demonstrating that informative cues canemanate from the developing organ lumen in the form of solid luminal material. The luminal material isproduced by the surrounding epithelium and helps to coordinate changes in shape and arrangement ofthe very same cells, resulting in correct lumen dimensions.
DOI: https://doi.org/10.1016/j.yexcr.2013.09.010
Posted at the Zurich Open Repository and Archive, University of ZurichZORA URL: https://doi.org/10.5167/uzh-81590Journal ArticleAccepted Version
Originally published at:Luschnig, Stefan; Uv, Anne (2014). Luminal matrices: An inside view on organ morphogenesis. Experi-mental Cell Research, 321(1):64-70.DOI: https://doi.org/10.1016/j.yexcr.2013.09.010
Page 1 of 21 Luschnig and Uv
Luminal matrices: An inside view on organ morphogenesis
Stefan Luschnig1*
and Anne Uv2*
1Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190,
CH-8057 Zurich, Switzerland
2Department of Medical Genetics, Institute of Biomedicine, Sahlgrenska Academy,
University of Gothenburg, SE-40530 Gothenburg, Sweden
*Correspondence: anne.uv@gu.se and stefan.luschnig@imls.uzh.ch
Keywords: apical extracellular matrix, organogenesis, tubulogenesis, lumen, chitin,
mechanical forces, luminal pressure
Page 2 of 21 Luschnig and Uv
Abstract
Tubular epithelia come in various shapes and sizes to accommodate the specific needs
for transport, excretion and absorption in multicellular organisms. The intestinal tract,
glandular organs and conduits for liquids and gases are all lined by a continuous layer
of epithelial cells, which form the boundary of the luminal space. Defects in epithelial
architecture and lumen dimensions will impair transport and can lead to serious organ
malfunctions. Not surprisingly, multiple cellular and molecular mechanisms
participate in controlling size and form of tubular epithelial structures. One intriguing
aspect of epithelial organ formation is the coordinate behaviour of individual cells as
they mould the mature lumen. Here, we focus on recent findings, primarily from
Drosophila, demonstrating that informative cues can emanate from the developing
organ lumen in the form of solid luminal material. The luminal material is produced
by the surrounding epithelium and helps to coordinate changes in shape and
arrangement of the very same cells, resulting in correct lumen dimensions.
Page 3 of 21 Luschnig and Uv
Introduction
Many developing epithelial organs start out as small tubular primordia that
will expand to give rise to mature functional organs. The cells constituting these
organ primordia are polarized along the apical-basal axis and connect to each other
via junctional complexes that maintain polarity and provide adhesive functions. While
the apical plasma membrane generally faces the lumen and exhibits specialized
secretory functions, the basal membrane rests on a surrounding basal lamina.
Additional cell layers, often of mesodermal origin, may encircle the tubular
epithelium to provide support and contractile forces to the organ. The subsequent
size-maturation of primordial organ lumina involves distinct and preprogramed
phases of growth, both in length and diameter, to attain dimensions optimal for organ
function. Such tube growth is mediated by highly coordinated changes in cell shape
and cell rearrangements, and it can be accompanied by cell proliferation as the entire
organ grows.
Key cellular processes involved in epithelial lumen morphogenesis include
membrane and protein trafficking, cytoskeletal changes, junction rearrangement,
growth and cell division. For instance, the addition of apical membrane to
accommodate rapid lumen diameter expansion can be driven by exocytosis, as in the
Drosophila tracheae [1, 2], or by reshuffling of intracellular membrane to the apical
surface, as in the excretory organ in C. elegans [3]. Oriented cell intercalation, cell
division and cell elongation also participate in regulating lumen dimensions during
size-maturation of the organ. In the developing Drosophila tracheae, axial tube
elongation relies on polarized cell shape changes along the tube axis [4, 5], while in
Xenopus embryos, the pronephric tubules elongate through rosette-based cell
intercalation [6]. The latter is similar to the highly stereotyped cell intercalation
Page 4 of 21 Luschnig and Uv
events observed during germband elongation in Drosophila [7], and both processes
depend on planar cell polarity (PCP) signalling. PCP appears to control the spatially
oriented cell rearrangements and the orientation of cell divisions along the renal tube
axis, and defects in this process have been proposed to cause cyst formation in
polycystic kidney disease (PKD) [8]. The stability and proper dimensions of lumina in
epithelial tubes are further supported by subapical actin and the intermediate filament-
based terminal web [9, 10].
An interesting problem is how the diverse cellular events are coordinated across
the epithelium to produce a correctly shaped lumen. Part of the answer may rely on
the transmission of forces within the tissue to produce coordinate global changes in
shape. Over the past years, much progress has been made in describing tissue and
organ morphogenesis as biomechanical processes [11]. The self-organizing features
of actin networks, the dynamics of actomyosin contractility, and the dynamic
remodelling of cell-cell junctions and ECM all contribute to the mechanical properties
of epithelial tissues. Tubular epithelia present a special case with regard to tissue
mechanics, as they form lumina that can provide an additional source for force
generation and integration to steer cellular behaviour in the surrounding epithelium.
Luminal hydrostatic pressure, for example, generated by liquid secretion or osmosis,
will exert a uniform force on the enclosing cells (Fig. 1A and 1B). Indeed, such
hydrostatic pressure was proposed to play important roles in lumen formation and
expansion in the gut [12], in Kupffer’s vesicle [13] and in brain ventricles [14] in
zebrafish, and in the excretory cell [15] and vulva [16] in C. elegans. Moreover, the
cylindrical geometry of tubular structures brings along physical constraints that are
distinct from those experienced by cells in planar epithelial sheets. Laplace’s law
states that circumferential surface tension on a pressurized cylinder is larger than axial
Page 5 of 21 Luschnig and Uv
surface tension. This force anisotropy can be exemplified by an over-boiled sausage,
which always bursts along its length (Fig. 1A). Thus, although the distribution and
scale of forces in tubular epithelia have not been well documented, luminal pressure
can in principle also generate planar asymmetry along the tube axis. Aside from
hydrostatic pressure, flow of the luminal content can generate shear stress that acts on
cells lining the apical surface of the tube wall. In the vascular and lymphatic systems,
such sheer stress activates mechanosensory signalling and leads to various cellular
effects, including changes in gene expression [17].
A recently discovered way of utilizing the lumen as a source of cues to
organize remodelling of the surrounding cells depends on solid luminal material. Such
luminal matrices are transiently deposited by the expanding epithelium and have
important roles in determining the size and shape of the organ, possibly by generating
and integrating mechanical forces across the luminal space. In the following, we
discuss functional aspects of such luminal matrices during Drosophila tubular organ
development, and consider the occurrence, molecular composition, and functions of
luminal components in various model systems. By integrating findings obtained in
Drosophila and in vertebrates, we highlight the potential general relevance of the
luminal matrix concept for diverse types of organs and organisms.
Drosophila tracheal tubes are shaped by a luminal chitin matrix
Maturation of epithelial lumen size has been extensively studied in the
Drosophila tracheal system, a branched tubular network built from a simple single-
layered epithelium. The two main tracheal tubes (dorsal trunks), with two to five cells
surrounding the lumen circumference (Fig. 2A), are initially formed as straight
narrow tubes running along the anterior to posterior axis of the animal. In the absence
Page 6 of 21 Luschnig and Uv
of further cell division, they undergo discrete growth phases leading to mature
diameter and length [18]. Diameter expansion involves substantial and rapid growth
of the luminal surface, whereas the outer tube diameter remains fairly constant (Fig.
2A). During this period, new apical membrane is added through apical secretion, and
animals with impaired secretion fail to expand the tracheal lumen while completing
many other morphogenetic processes [1, 2]. Tracheal tube elongation is controlled
independently of diametric expansion and requires the tyrosine kinase Src42 for
polarized cell shape changes in the axial dimension of the tubes [4, 5]. Src42 could be
involved in sensing anisotropic mechanical forces or in translating such mechanical
cues into oriented cell elongation by regulating adherens junction remodelling [4] and
actin polymerization through effects on the formin DAAM [5].
In case of the embryonic tracheal tubes, diametric growth of the lumen is
driven by secretion to increase the apical cell surface area [1]. Yet, genes involved in
chitin synthesis and chitin organization are essential for uniform diameter expansion.
Chitin, a polymer of beta-1,4-N-Acetylglucosamine (GlcNAc), is produced by
transmembrane chitin synthases that convert cytoplasmic UDP-GlcNAc to long
polysaccharide chains that extrude into the apical extracellular space. Just prior to
diameter expansion, the tracheal cells begin to deposit chitin to form a transient fibre-
like filament that fills the luminal space during diameter growth (Fig. 2A). Strikingly,
in mutant animals that lack tracheal chitin, the tracheal lumen develops severe local
dilations and constrictions along the entire tube length. (Fig. 2A) [19, 20]. Inhibition
of chitin synthesis, or expression of an apically secreted chitinase, produces similar
effects, arguing that the intraluminal chitin functions to shape the lumen.
An important feature of chitin is the ability to form matrices with different
physical properties. Nascent chitin chains form microfibrils of about 20 chains that
Page 7 of 21 Luschnig and Uv
can organize into different types of structures depending on associated proteins [21].
Correct organization of chitin in the tracheal lumen is essential for its function, since
defects in chitin structure, as observed in mutants for knickkopf (knk) or retroactive
(rtv), also lead to an uneven lumen diameter, similar to what is seen upon loss of
chitin [19, 22]. Knk and Rtv are secreted membrane-bound proteins required for
correct chitin organization both in the tracheal lumen and later in the apical cuticle.
The chitin matrix therefore appears to provide a physical scaffold to shape the organ,
consistent with the tube defects upon fragmentation of chitin chains [20]. The matrix
conceivably attaches to the apical surface of surrounding tracheal cells, thereby acting
to simultaneously push and hold back the tube wall and mould the lumen into a shape
determined by the form and rigidity of the matrix itself (Fig. 1B). Despite intensive
mutagenesis screens to detect new tracheal tube size genes, there is no report yet of a
candidate molecule that can mediate attachment between the chitinous matrix and the
apical cell surface. However, chitin synthases are processive enzymes that remain
bound to the growing polymer through multiple polymerization steps, and, in analogy
with cellulose synthases, it is possible that chitin synthase subunits form
supramolecular complexes, allowing the nascent chitin chains to spontaneously form
microfilaments [21]. Such microfilaments, being attached to the chitin synthases at
one end and incorporated into the chitinous matrix at the other, could effectively serve
as anchors.
Proteins embedded in chitinous matrixes can alter the structure of the matrix
and modulate its stiffness, elasticity and accessibility to degradation [21].
Furthermore, chitin fibrils can be enzymatically modified by deacetylation, which
alters the chemical and mechanical properties of the chitin polymer. Two secreted
chitin deacetylases, Serpentine (Serp) and Vermiform (Verm), contain chitin binding
Page 8 of 21 Luschnig and Uv
and chitin deacetylase domains [23, 24]. Mutations in these genes affect the structure
of both the cuticular and tracheal chitinous matrices. Intriguingly, tracheal tube
diameter is normal in animals that lack either protein, but the tubes grow excessively
in length. The over-elongated tracheal tubes in serp and verm mutants suggest that the
chitin matrix acts to limit tube elongation, and that the proteins affect the longitudinal
tensional strength of the matrix. Recently, two other proteins with chitin-binding
domains, Obst-A and Gasp, were shown to be required for full diameter expansion of
the tracheal lumen [25, 26]. Given that the proteins affect the assembly of chitinous
matrices, the proteins might increase the diametric tensional force of the luminal
matrix needed for full diametric lumen expansion.
To summarize, research on tracheal tube maturation shows that cell intrinsic
mechanisms, such as apical secretion and oriented cell elongation, are prerequisites
for lumen growth, and that luminal chitin matrices provide essential physical
constraints serving to coordinate changes in cell shape to adjust both tube diameter
and length.
A non-chitinous matrix drives diameter expansion of the Drosophila hindgut
While a main component of the tracheal luminal matrix is chitin, vertebrates
do not synthesize chitin. Also in Drosophila, intraluminal chitin is detected
exclusively in the developing tracheal network. Thus, a simple extrapolation of the
findings from the Drosophila trachea is not possible based on molecular homologues.
However, it was recently shown that the large luminal glycoprotein Tenectin (Tnc)
forms a luminal matrix that acts to drive tube diameter expansion in the developing
Drosophila hindgut [27]. The Tnc matrix spans the lumen and causes dose-dependent
expansion, suggesting that it generates a luminal physical force during tube growth.
Page 9 of 21 Luschnig and Uv
The embryonic hindgut consists of about 700 epithelial cells surrounded by
visceral muscle cells. After formation of the primordial hindgut tube, which is shaped
like the shaft of an umbrella, the tube grows in length and diameter over a three-hour
period to attain its final dimensions (Fig. 2B). Lumen diameter expansion is not
uniform along the tube axis, but the “crook handle” of the umbrella shaft (small
intestine) expands to a larger extent than the straight part (large intestine). As no cell
division takes place during lumen growth, the process is mediated by increase in cell
size, flattening of the cells along the apico-basal axis and rearrangement of cells [28].
While Tnc forms a continuous fibrillar material in the entire hindgut lumen, Tnc
expression levels are higher in the small intestine than in the large intestine (Fig. 2B)
[27, 29]. In tnc mutants, the hindgut tube diameter remains narrow, while over-
expression of Tnc leads to diametric overexpansion in a dose-dependent fashion (Fig.
1B). At the cellular level, Tnc promotes an increase in apical cell surface, oriented
cell elongation along the tube perimeter and cell intercalation to yield more cells
along the lumen perimeter [27]. These effects are similar to those caused by
hydrostatic pressure during inflation of the zebrafish brain ventricle [14], expansion
of the mouse blastocyst [30], and growth of renal cysts in vitro [31, 32]. Given that
Tnc contains two large mucin-domains rich in serine and threonine that are substrates
for O-glycosylation, it is possible that hydration of Tnc in the lumen mediates the
formation of a gel-like matrix that can exert a distending force on the surrounding
tube wall. Consistent with this idea, Tnc exerts its function as a secreted protein
within the lumen, and it is able to cause abnormal tube diameter when misexpressed
in other tubular organs. Moreover, at sites of Tnc secretion, the protein forms a
lumen-spanning complex with low mobility, causing local dilation. It therefore seems
Page 10 of 21 Luschnig and Uv
that Tnc can cause regional effects on diameter expansion dependent on its level of
expression along the tube axis [27].
Although both Tnc- and chitin-containing luminal matrices are important to
shape epithelial structures, the two matrices exert different functions during tube
diameter expansion. The former drives tube diameter expansion in a dose-dependent
manner that can be explained by an increased intraluminal pressure, whereas the
chitin matrix does not promote expansion, but rather maintains a uniform lumen
during secretion-driven diameter expansion. In this instance, specific attachment of
chitin to the surrounding epithelium is likely to be involved (Fig. 1B).
Additional luminal cues in epithelial organ morphogenesis
Large glycoproteins are common among species, and there is evidence that
glycosylated components are transiently present in the lumina of different types of
developing epithelial organs. The application of fluorescently conjugated lectins to
detect various O-linked and N-linked glycans in Drosophila embryos revealed
staining in the lumina of the salivary glands, fore- and hindgut, and the tracheae [33].
Moreover, an antibody against the Tn antigen (GalNAcα–Ser/Thr) that detects O-
glycans, stained the lumina of the same organs [33]. Luminal lectin staining in
epithelial organs during lumen growth is not restricted to the fly embryo, but has also
been documented for the embryonic kidney [34] and lung [35] in vertebrates. Notably,
during the initial formation of parabronchi and atria in chick embryos, various lectins
stained the surface and cytoplasmic granules of the lining epithelial cells, but in
subsequent phases, the parabronchial lumen and the atrial cavities were characterized
by the presence of lectin-reactive material [35]. This lectin-reactive material
disappeared a few days before birth, which would be consistent with a function during
Page 11 of 21 Luschnig and Uv
lumen growth. In the same way, an electron-dense material is detectable in the
embryonic C. elegans excretory cell lumen after formation of the luminal surface. The
matrix is present during lumen elongation and ramification, and disappears before
hatching, when intracellular electron-dense material appears in the subapical cortex
[36]. One component of the excretory cell luminal matrix is the mucin-like protein
let-653 [36, 37]. In let-653 mutants the worm’s single-celled excretory canals swell
into large cysts. Although the molecular mechanism is not known, it is conceivable
that the let-653 matrix and the luminal chitin filament in the Drosophila trachea
provide similar functions in modelling or stabilizing luminal shape.
In Drosophila, Tnc is found in the developing lumina of several organs, but it
appears that Tnc contributes to detectable luminal O-glycans only in the hindgut.
Thus, additional luminal O-glycosylated proteins are probably abundant in other
organ lumina. These might correspond to a subset of mucin-like proteins that are
dynamically expressed in embryonic epithelial organs during size maturation [38],
and to other unknown glycoproteins. Luminal proteins might also contribute to
shaping the lumen of the salivary gland in Drosophila [39]. Ultrastructural analysis of
the wild-type salivary gland shows that the apical cell surfaces surround a relatively
large luminal space filled with a fibrillar matrix. Embryos that lack SG1 and SG2, two
subunits of ER-resident prolyl 4-hydroxylase that hydroxylates prolines in secreted
and transmembrane proteins, show a reduced volume and altered structure of salivary
gland secretions. These altered secretions are associated with regions of tube dilation
and constriction and intermittent tube closures, suggesting that modification of
luminal proteins by SG1 and SG2 is required for formation of an expanded fibrillar
matrix to maintain an open and uniform tube [39]. Moreover, two secreted Zona
Pellucida (ZP) proteins, Piopio (Pio) and Dumpy (Dp), are deposited in the tracheal
Page 12 of 21 Luschnig and Uv
lumen and are essential for maintaining integrity of the tubes during tracheal cell
intercalation [40]. Interestingly, Pio and Dp, a giant protein of 2.5 MDa, are also
required for maintaining stable attachment between epithelial sheets in the fly wings
and for epidermal-cuticle attachment, suggesting a general function of these proteins
in determining mechanical properties of epithelia.
Apart from components of the aforementioned luminal matrices, luminal
glycoproteins can facilitate the separation of apical membranes during lumen
formation. It has been proposed that membrane detachment might involve steric
hindrance of cell-cell adhesion by large transmembrane glycoproteins [41]. Indeed,
the initial separation of apical membranes during aortic tube development in the
mouse requires the apical sialomucin Podocalyxin [42], whose negatively charged
sialic acid moieties are thought to cause electrostatic repulsion of the apical surfaces.
In the Drosophila retina, a large predicted proteoglycan called Eyes Shut (Eys) [43] is
apically secreted by the photoreceptor cells that form a neuroepithelium. Clusters of
photoreceptor cells enclose with their apical surfaces a channel-like extracellular
space called the interrhabdomeric space, into which Eys is deposited. Eys is required
to separate the apical membranes of the photoreceptors to form the interrhabdomeric
space, but its exact mechanism of action is not known.
Along with continued research to reveal new protein functions in epithelial
organ morphogenesis, the list of luminal components with roles in epithelial
remodelling will likely expand. Their functional characterization is promising to
reveal further insights into how organ lumina contribute chemical and mechanical
cues during tissue remodelling.
Page 13 of 21 Luschnig and Uv
Perspectives
Apical extracellular matrices have previously been described mainly in the context of
their roles in organ physiology, protecting the epidermis and internal epithelial
surface from physical and chemical damage, dehydration and infection. With this
review we highlight important functions of apical ECMs in organ morphogenesis,
which have become evident only over the past decade. A key concept is that the
luminal material provides a global cue to the epithelium and is thereby capable of
coordinating cell behaviour over long distances within a particular organ. Recent
work has shown that luminal matrices can be built from different types of
macromolecules, such as long polysaccharides or large glycoproteins, and that
different types of matrices have different properties and effects on the surrounding
epithelium. Unlike hydrostatic pressure, which is isotropic, solid luminal matrices can
exert differential forces along the tube axis, and these forces can be generated also at
developmental stages when epithelial paracellular barrier functions (which are
essential to generate luminal hydrostatic pressure) are not yet established. A luminal
matrix can also act as a scaffold for the surrounding cells and, through attachments to
the apical surface of the tube wall, impose a restraint on diametric expansion and tug
or hold back tube elongation (Fig. 1B). Such force integration along the luminal
matrix may facilitate the coordination of cell behaviour across the epithelium. It
currently remains largely unexplored how cells sense and respond to the mechanical
cues from luminal matrices. The deformation (contraction, stretching) imposed by the
luminal matrix will plausibly challenge load-carrying adhesions and structural
elements beyond the elasticity range of the tissue, resulting in plastic tissues changes.
Further studies will be required to assess the scale and distribution of mechanical
forces within organ lumina, and to elucidate which cellular elements mediate
Page 14 of 21 Luschnig and Uv
resistance and adaptations to these forces. This will involve characterizing and
manipulating the level of stretching, compression or relaxation that is imposed by
luminal matrices, as well as studying the biological mechanisms of how mechanical
cues are translated into intracellular changes.
Acknowledgments
We would like to apologize to colleagues whose work could not be cited due to space
limitations.
Research in AU’s laboratory is supported by the Swedish Research Council (VR-M)
and the Swedish Cancer Society. Research in SL’s laboratory is supported by the
Swiss National Science Foundation (SNF 31003A_141093_1), the University of
Zürich, and the Kanton Zürich.
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Figure legends
Figure 1. Physical cues in epithelial tube expansion
A) Internal isotropic pressure in a cylinder will produce hoop stress (σH) and
longitudinal stress (σL) in the tube wall. The hoop stress is larger than the longitudinal
stress, as illustrated by the longitudinally ruptured skin of an over-boiled sausage.
B) Three ways that physical luminal cues can act during diameter expansion of a
tubular primordium. Left: Hydrostatic pressure generates equal force normal to the
lumen surface. Depending on the magnitude and duration of force and on the
mechanical properties of the tissue, the resulting deformation can lead to expansion of
the entire tube diameter. Middle: Apical membrane growth results in lumen dilation.
A rigid luminal matrix serves as a scaffold that holds on to the lumen surface and
supports uniform lumen diameter growth. Right: A luminal matrix generates an
internal pressure. The low mobility of the matrix inside the lumen facilitates
differential lumen dilation along the tube axis, depending on the local amount of
matrix deposition.
Figure 2. Roles for luminal matrices in diametric expansion of the Drosophila
tracheae and hindgut.
A) Top, left: The lumen of tracheal tubes grows by apical membrane growth and cell
flattening. The apical surface is drawn in magenta and the luminal matrix in green.
Top, middle: Transmission electron microscopy reveals the secretory activity of
tracheal cells early during expansion (top panel) and the presence of solid material in
the lumen centre during dilation. Top, right: Live imaging of tracheal cells expressing
cytoplasmic GFP (blue) and the luminal chitin-binding protein, Verm::RFP (green)
Page 21 of 21 Luschnig and Uv
shows how the luminal component fills the lumen during expansion. Bottom: The
luminal chitin matrix, detected by a fluorescently conjugated chitin-binding protein
(green), forms a filamentous matrix inside the lumen, which is delineated by labelling
for the apical protein, Crumbs (Crb; magenta). In kkv mutants, chitin is missing and
the tubes develop local dilations and constrictions.
B) Top: The lumen of the small (Si) and large intestine (Li) parts of the hindgut is
drawn to scale before (stage 14) and after (stage 16) lumen diameter expansion. The
hindgut lumen in tnc mutants remains narrow. Bottom, left: Tnc (green) fills the
lumen of the hindgut and appears as a striated matrix. Bottom, right: Over-expression
of Tnc in the hindgut causes excess lumen dilation, both of inner (Crb; magenta, solid
white line) and outer (Dystroglycan; blue, dashed white line) diameter, compared to
the wild type.
Manus.pdfFigure1_revised copyFigure2_revised-01 copy
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